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1.
Genet Mol Res ; 14(4): 14291-9, 2015 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-26600487

RESUMEN

The angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been reported to be associated with digestive system cancer; however, the results from previous studies have been conflicting. The present study aimed to investigate the association between the ACE I/D polymorphism and the risk of digestive system cancer using a meta-analysis of previously published studies. Databases were systematically searched to identify relevant studies published prior to December 2014. We estimated the pooled OR with its 95%CI to assess the association. The meta-analysis consisted of thirteen case-control studies that included 2557 patients and 4356 healthy controls. Meta-analysis results based on all the studies showed no significant association between the ACE I/D polymorphism and the risk of digestive system cancer (DD vs II: OR = 0.85, 95%CI = 0.59-1.24; DI vs II: OR = 0.94, 95%CI = 0.78-1.15; dominant model: OR = 0.96, 95%CI = 0.81- 1.15; recessive model: OR = 1.06, 95%CI = 0.76-1.48). Subgroup analyses by race and cancer type did not detect an association between the ACE I/D polymorphism and digestive system cancer risk. However, when the analyses were restricted to smaller studies (N < 500 patients), the summary OR of DI vs II was 0.80 (95%CI = 0.66-0.97). Our analyses detected a possibility of publication bias with a misestimate of the true association by smaller studies. Overall, meta-analysis results suggest the ACE I/D polymorphism might not be associated with susceptibility to digestive system cancer. Further large and well-designed studies are needed to confirm these conclusions.


Asunto(s)
Neoplasias del Sistema Digestivo/genética , Peptidil-Dipeptidasa A/genética , Estudios de Casos y Controles , Neoplasias del Sistema Digestivo/enzimología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Mutación INDEL , Polimorfismo Genético , Sesgo de Publicación , Factores de Riesgo
2.
J Clin Invest ; 100(4): 829-38, 1997 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-9259582

RESUMEN

Human respiratory epithelium expresses inducible nitric oxide synthase (iNOS) continuously in vivo, however mechanisms responsible for maintenance of expression are not known. We show that IFNgamma is sufficient for induction of iNOS in primary human airway epithelial cells (HAEC) in vitro, and IL-4 potentiates IFNgamma-induced iNOS expression in HAEC through stabilization of iNOS mRNA. IFNgamma/IL-4- induced iNOS expression in HAEC was delayed in onset and prolonged with expression up to 1 wk. Removal of overlying culture media resulted in loss of expression, while transfer of conditioned media induced iNOS mRNA in other HAEC. IFNgamma and IL-4 stimulation activated STAT1 and STAT6 in HAEC, but conditioned media transfer to HAEC produced even higher levels of STAT1 activation than achieved by direct addition of cytokines. Although cytokine induction of iNOS was dependent on new protein synthesis, conditioned media induction of iNOS in HAEC was not. Further, removal of overlying culture media from cells at different times after cytokine stimulation demonstrated that mediator synthesis and/or secretion important for induction and maintenance of iNOS occurs early after cytokine stimulation. In conclusion, a combination of IFNgamma/ IL-4, which occurs naturally in the lung epithelial lining fluid, leads to maintenance of iNOS expression in human airway epithelium through production of soluble mediators and stabilization of mRNA.


Asunto(s)
Bronquios/metabolismo , Interferón gamma/farmacología , Interleucina-4/farmacología , Óxido Nítrico Sintasa/metabolismo , Adolescente , Adulto , Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Bronquios/química , Bronquios/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Complejo CD3/análisis , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Cicloheximida/farmacología , Epitelio/química , Femenino , Regulación de la Expresión Génica , Humanos , Inmunohistoquímica , Interferón gamma/análisis , Interleucina-4/análisis , Queratinas/análisis , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factores de Tiempo , Vimentina/análisis , omega-N-Metilarginina/farmacología
3.
Environ Health Perspect ; 106 Suppl 5: 1119-24, 1998 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9788885

RESUMEN

Nitric oxide is an important mediator of inflammatory responses in the lung and a key regulator of pulmonary vascular and bronchomotor tone. We have shown that the inducible nitric oxide synthase (iNOS) isoform is continuously expressed in human airway epithelium at mRNA and protein/activity levels in vivo. However, removal of epithelial cells from the in vivo airway environment resulted in rapid loss of iNOS expression, which suggested that expression is dependent upon conditions and/or factors present in the airway. To investigate the mechanisms responsible for maintenance of expression in vivo, we evaluated regulation of iNOS expression in primary human airway epithelial cells. Interferon-gamma (IFN-gamma) was sufficient for induction of iNOS in primary human airway epithelial cells (HAEC) in vitro, and interleukin-4 (IL-4) potentiated the expression through stabilization of iNOS mRNA. The IFN-gamma/IL-4-induced iNOS expression in HAEC was delayed in onset and prolonged with expression up to 1 week. Furthermore, transfer of overlying culture media [conditioned media (CM)] to other HAEC led to iNOS induction. Interestingly, IFN-gamma/IL-4 induction of iNOS was dependent on new protein synthesis, whereas CM induction of iNOS was not. IFN-gamma and IL-4 activated signal transducers and activators of transcription (STAT1 and STAT6) in HAEC, but CM transfer to HAEC produced even higher levels of STAT1 activation than achieved by direct addition of cytokines. Thus, IFN-gamma/IL-4, which occurs in human lung lining fluid, led to iNOS expression in human airway epithelium through production of soluble mediators and stabilization of mRNA.


Asunto(s)
Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Sistema Respiratorio/enzimología , Epitelio/enzimología , Expresión Génica , Humanos , Técnicas In Vitro , Interferón gamma/farmacología , Interleucina-4/farmacología , Óxido Nítrico Sintasa de Tipo II , Estabilidad del ARN/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes
4.
J Immunol ; 164(11): 5970-80, 2000 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-10820280

RESUMEN

Evidence supporting increased nitric oxide (NO) in asthma is substantial, although the cellular and molecular mechanisms leading to increased NO are not known. Here, we provide a clear picture of the events regulating NO synthesis in the human asthmatic airway in vivo. We show that human airway epithelium has abundant expression of NO synthase II (NOSII) due to continuous transcriptional activation of the gene in vivo. Individuals with asthma have higher than normal NO concentrations and increased NOSII mRNA and protein due to transcriptional regulation through activation of Stat1. NOSII mRNA expression decreases in asthmatics receiving inhaled corticosteroid, treatment effective in reducing inflammation in asthmatic airways. In addition to transcriptional mechanisms, post-translational events contribute to increased NO synthesis. Specifically, high output production of NO is fueled by a previously unsuspected increase in the NOS substrate, l -arginine, in airway epithelial cells of asthmatic individuals. Finally, nitration of proteins in airway epithelium provide evidence of functional consequences of increased NO. In conclusion, these studies define multiple mechanisms that function coordinately to support high level NO synthesis in the asthmatic airway. These findings represent a crucial cornerstone for future therapeutic strategies aimed at regulating NO synthesis in asthma.


Asunto(s)
Asma/metabolismo , Óxido Nítrico/biosíntesis , Procesamiento Proteico-Postraduccional/inmunología , Transcripción Genética/inmunología , Adulto , Empalme Alternativo , Arginina/metabolismo , Asma/enzimología , Asma/inmunología , Bronquios/enzimología , Bronquios/metabolismo , Líquido del Lavado Bronquioalveolar/inmunología , Proteínas de Unión al ADN/metabolismo , Células Epiteliales/enzimología , Células Epiteliales/metabolismo , Femenino , Fluocinolona Acetonida/análogos & derivados , Fluocinolona Acetonida/farmacología , Humanos , Interferón gamma/metabolismo , Janus Quinasa 1 , Masculino , Nitratos/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Proteínas Tirosina Quinasas/metabolismo , ARN Mensajero/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT1 , Transactivadores/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
5.
Proc Natl Acad Sci U S A ; 92(17): 7809-13, 1995 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-7544004

RESUMEN

Nitric oxide (NO) is an important mediator of inflammatory responses in the lung and a key regulator of bronchomotor tone. An airway NO synthase (NOS; EC 1.14.13.39) has been proposed as a source of endogenous NO in the lung but has not been clearly defined. Through molecular cloning, we conclusively demonstrate that NO synthesis in normal human airways is due to the continuous expression of the inducible NOS (iNOS) isoform in airway epithelial cells. Although iNOS mRNA expression is abundant in airway epithelial cells, expression is not detected in other pulmonary cell types, indicating that airway epithelial cells are unique in the continuous pattern of iNOS expression in the lung. In situ analysis reveals all airway epithelial cell types express iNOS. However, removal of epithelial cells from the in vivo airway environment leads to rapid loss of iNOS expression, which suggests expression is dependent upon conditions and/or factors present in the airway. Quantitation of NOS activity in epithelial cell lysates indicates nanomolar levels of NO synthesis occur in vivo. Remarkably, the high-level iNOS expression is constant in airway epithelium of normal individuals over time. However, expression is strikingly decreased by inhaled corticosteroids and beta-adrenergic agonists, medications commonly used in treatment of inflammatory airway diseases. Based upon these findings, we propose that respiratory epithelial cells are key inflammatory cells in the airway, functioning in host defense and potentially playing a role in airway inflammation.


Asunto(s)
Aminoácido Oxidorreductasas/biosíntesis , Bronquios/enzimología , Óxido Nítrico/biosíntesis , Adulto , Aminoácido Oxidorreductasas/metabolismo , Secuencia de Bases , Bronquios/citología , Bronquios/patología , Líquido del Lavado Bronquioalveolar , Células Cultivadas , Clonación Molecular , Cartilla de ADN , Inducción Enzimática , Células Epiteliales , Epitelio/enzimología , Epitelio/patología , Femenino , Expresión Génica , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Masculino , Datos de Secuencia Molecular , Óxido Nítrico Sintasa , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Proteínas Recombinantes/biosíntesis , Valores de Referencia
6.
Am J Physiol ; 272(1 Pt 1): L148-54, 1997 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-9038914

RESUMEN

To investigate the antioxidant response of respiratory epithelium to the chronic airway inflammation in asthma, the major intracellular antioxidants [copper and zinc-containing superoxide dismutase (Cu,Zn-SOD) and manganese-containing SOD (Mn-SOD), catalase, and glutathione peroxidase] were quantitated in bronchial epithelial cells of healthy control and asthmatic individuals. Although catalase and glutathione peroxidase in bronchial epithelium of asthmatics were similar to control SOD activity in asthmatics not on inhaled corticosteroid (-CS) was lower than asthmatics on inhaled corticosteroid (+CS) and controls. Investigation of Mn-SOD and Cu,Zn-SOD activities revealed that the lower SOD activity in asthmatics -CS was because of decreased Cu,Zn-SOD activity. However, Mn-SOD and Cu,Zn-SOD mRNA and protein levels were similar among asthmatics -CS, asthmatics +CS, and controls. Importantly, Cu,Zn-SOD specific activity in asthmatics -CS was decreased in comparison with control and asthmatics +CS. Furthermore, in paired comparisons of asthmatics -CS and +CS, inhaled corticosteroids resulted in normalization of bronchial epithelial Cu,Zn-SOD specific activity. These findings suggest loss of Cu,Zn-SOD activity in asthma is related to inflammation, perhaps through oxidant inactivation of Cu,Zn-SOD protein.


Asunto(s)
Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Asma/enzimología , Bronquios/enzimología , Superóxido Dismutasa/metabolismo , Administración por Inhalación , Corticoesteroides/administración & dosificación , Adulto , Asma/patología , Bronquios/efectos de los fármacos , Bronquios/patología , Epitelio/efectos de los fármacos , Epitelio/enzimología , Epitelio/patología , Femenino , Expresión Génica , Humanos , Masculino , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Superóxido Dismutasa/genética
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